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Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

573 Background: Pre-operative radiotherapy (RT) for PA has the potential to reduce positive surgical margin rates and increase pathologic tumor response, which has been associated with improved survival. Increasing the BED can improve local control and overall survival for patients with unresectable PA. Use of stereotactic body radiation therapy (SBRT) to achieve a higher BED has been limited by toxicity to adjacent radiosensitive structures, but this can be mitigated by MRgRT. We describe our use of MRgRT prior to potentially curative resection of localized PA. Methods: We performed a single institution retrospective analysis of all patients with localized PA who received high BED SBRT on the MR Linac followed by surgical resection with curative intent. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events, version 5.0. Tumor response was evaluated according to the College of American Pathologists tumor regression grading criteria (CAP-TRG), ranging from CAP 0 indicating pathologic complete response to CAP grade 3 indicating no response. Ordinal logistic regression model was used to assess the association between time from RT to surgery and TRG. Follow up included MRI or CT scans at least every three months. Results: We analyzed 26 patients with borderline resectable (80.8%), locally advanced (11.5%), and resectable (7.7%) tumors who received high BED MRgRT followed by surgical resection. Median age at diagnosis was 68 years (34 - 86). Most patients received chemotherapy (80.8%) prior to RT, with 81% of these receiving FOLFINIRNOX and 19% receiving gemcitabine/nab-paclitaxel. All patients received MR-guided high BED SBRT to a median dose of 50 Gy (40 - 50) in 5 fractions. On-table adaptive replanning was performed in 88% of patients, with 74% having all 5 fractions adapted. No acute grade 2+ toxicity associated with RT was observed. The median time to resection was 50 days (37 – 115), and the procedure types included: Whipple (69%), distal (23%), or total pancreatectomy (8%). The R0 resection rate was 96% and no perioperative deaths occurred within 90 days. Complete (0) or near-complete (1) pathologic response was observed in 35% of cases and the time from RT to surgery was positively associated with TRG (R2= 0.22, p = 0.0003). The median follow-up after RT was 16.5 months (3.9- 26.2) during which 9 patients recurred, and 3 patients died of disease. The derived median progression-free survival from RT was 13.2 months. Conclusions: These initial pathology outcomes following high BED MR-guided SBRT are encouraging and suggest that the time from SBRT to surgical resection is associated with response. This finding is consistent with results from other preoperative GI tumor sites and results from prospective studies using high BED SBRT with MRI guidance in combined modality therapy against PA are eagerly awaited.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

1079 Background: Brain metastases (BM) are a common and fatal complication of breast cancer but survival varies widely based on various prognostic factors (PF). Hence, patient counseling and therapeutic decisions should be individualized. We previously published a prognostic index (Breast GPA) based on cohort A (1985-2007, n = 642), updated it with tumor subtype in cohort B (1993-2010, n = 400) and are now updating it with a larger contemporary cohort (C). Methods: A multi-institutional (19) multi-national (3) retrospective database of 2473 breast cancer patients with BM diagnosed from 1/1/2006-12/31/2017 was created and compared to our prior cohorts. Demographic, clinical, molecular factors, tumor subtype and treatment were correlated with survival. Kaplan-Meier survival estimates were calculated and compared with log-rank tests. Results: The median survival (MS) for cohorts A, B and C improved over time [12, 14 and 16 mo, respectively ( < 0.01)] despite the subtype distribution becoming less favorable: Luminal B (ER/PR/HER2+) decreased from 26% to 21%; HER2 (HER2+/ER/PR-) decreased from 31% to 17%, Luminal A (ER/PR+/HER2-) increased from 20% to 31%; Basal (ER/PR/HER2-) was unchanged at 24%.MS by subtype improved from 21 to 27 mo in Luminal B, 18 to 25 mo in HER2, 10 to 14 mo in Luminal A and 6 to 9 mo in Basal tumors. The number of BM was 1 in 35%, ≤4 in 67% and > 10 in 18%. PF significant for survival were tumor subtype, age, KPS, number of BM and extracranial metastases (ECM) (all < 0.01). Surprisingly, Hispanic women (7%) showed improved survival (p < 0.01). BRCA1 was mutated in 57/533 (11%) and those patients showed a trend (0.16) toward improved survival. Treatment patterns have changed: the use of whole brain radiation therapy decreased from 71% to 67% to 47% in cohorts A, B and C, respectively. Conclusions: Despite the shift to less favorable tumor subtypes, MS has improvedbut varies widely by diagnosis-specific PF. Compared to prior cohorts, number of BM and ECM were identified as new PF. Ethnic, genetic and treatment differences between the eras are apparent. The updated Breast GPA, based on these data, and the correlation between BRCA1 and tumor subtype will be presented.

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of ≤ 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of .05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P = .28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P = .039). Survival in the three groups was 93%, 94%, and 93%, respectively (P = .93). CONCLUSION: In women with tumors ≤ 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.